Field of the Invention
This disclosure relates to novel PD-L1 antibodies and methods for using the same for detecting PD-L1 polypeptides in a biological sample. PD-L1 antibodies also are useful to evaluate the efficacy of a particular therapeutic agent in a subject diagnosed as having a PD-L1-related medical condition.
Description of Related Art
The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art.
Programmed death 1 (PD-1) is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. The initial members of the family, CD28 and ICOS, were discovered by functional effect on augmenting T cell proliferation following the addition of monoclonal antibodies (Hutloff et al., Nature 397:263-266 (1999); Hansen et al. Immunogenics 10:247-260 (1980)). Two cell surface glycoprotein ligands for PD-1 have been identified, PD-L1 and PD-L2, and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1 (Freeman et al., J Exp Med 192:1027-34 (2000); Latchman et al., Nat Immunol 2:261-8 (2001); Carter et al., Eur J Immunol 32:634-43 (2002); Ohigashi et al., Clin Cancer Res 11:2947-53 (2005)). Both PD-L1 (B7-H1) and PD-L2 (B7-DC) are B7 homologs that bind to PD-1, but do not bind to other CD28 family members.
Human PD-L1 encodes a 290 amino acid (aa) type I membrane precursor protein with a putative 18 aa signal peptide, a 221 aa extracellular domain, a 21 aa transmembrane region, and a 31 aa cytoplasmic domain. Human PD-L1 is constitutively expressed in several organs such as heart, skeletal muscle, placenta and lung, and in lower amounts in thymus, spleen, kidney and liver. PD-L1 expression is upregulated in a small fraction of activated T and B cells and a much larger fraction of activated monocytes. PD-L1 expression is also induced in dendritic cells and keratinocytes after IFN gamma stimulation.
The PD-L1-PD1 pathway is involved in the negative regulation of some immune responses and may play an important role in the regulation of peripheral tolerance. Interaction of PD-L1 with PD1 results in inhibition of TCR-mediated proliferation and cytokine production. PD-L1 has been suggested to play a role in tumor immunity by increasing apoptosis of antigen-specific T-cell clones (Dong et al. Nat Med 8:793-800 (2002)). Indeed, PD-L1 expression has been found in several murine and human cancers, including human lung, ovarian and colon carcinoma and various myelomas (Iwai et al. PNAS 99:12293-7 (2002); Ohigashi et al. Clin Cancer Res 11:2947-53 (2005)). Thus, measuring the amount of PD-L1 protein in biological samples may aid in the early detection of cancer pathologies and may help assess the efficacy and durability of investigational drugs that inhibit the binding of the PD-L1 protein.
However, the use of PD-L1 protein expression as an accurate predictor for cancer and/or the efficacy of anti-PD-1 and anti-PD-L1 directed therapies remains challenging. Many commercially available antibodies directed to PD-L1 cross-react with other proteins and/or exhibit non-specific histological staining, thereby making them unreliable diagnostic reagents. Furthermore, conflicting results have been observed when comparing PD-L1 antibodies targeting the extracellular domain versus the intracellular domain. McLaughlin et al., J. Clin Oncol 32:5 (2014). Moreover, the evaluation of PD-L1 expression in non-small cell lung cancer samples using commercially available antibodies such as E1L3N® (Cell Signaling Technology, MA), 5H1 (Dong et al., Nat Med. 8:793-800 (2002)) and E1J2J, yielded discordant results. McLaughlin et al., J. Clin Oncol 32:5 (2014).